應用核磁共振儀探討全氟癸酸暴露對大鼠之多器官脂質影響

Abstract

全氟與多氟烷基物質（PFASs）是一類廣泛應用於工業和消費產品中的合成化學品。先前的研究已經指出PFASs與代謝症候群，例如脂質代謝紊亂以及其他不良健康影響的相關性。全氟癸酸（PFDA）是PFASs的一種，最近的研究顯示約70%的臺灣兒童血清中檢測到了PFDA。然而，對PFDA的研究有限，且其毒性和潛在機制仍不清楚。因此，本研究旨在利用脂質體學方法，探討大鼠多個器官對PFDA暴露的脂質反應，以確定目標器官並理解其脂質效應及可能的健康不良影響。 本研究採用18隻Sprague-Dawley雄性大鼠作為模型，分別每天以每公斤體重0、0.5和1毫克的PFDA進行管胃餵食持續21天，測量體重和器官重量變化。隨後犧牲大鼠，並收集與萃取肝臟、心臟、腎臟、肺臟、胰臟和睪丸的組織樣本，採用核磁共振為基礎的脂質體學方法來識別關鍵脂質反應。取得的核磁共振圖譜會經過圖譜前處理並進行多變量包含偏最小平方法判別分析（PLS-DA）和單變量分析，最後進行數據及生物資訊的解釋。 暴露後，肝臟重量與肝臟重量與體重之比例顯著增加。以PLS-DA進行的脂質分析顯示，肝臟和心臟對PFDA暴露的反應具有劑量依賴性。肝臟中膽固醇、磷脂醯膽鹼（PC）/磷脂醯乙醇胺（PE）的濃度降低，而脂肪酸（FA）濃度增加。在心臟中，甘油脂（GLs）濃度降低，而甘油磷脂（GPs）濃度增加。這些脂質改變在肝臟中可能與細胞膜功能的變化與粒線體功能障礙有關，而在心臟中則是與心血管相關疾病有關。然而，在肺、腎臟、胰臟和睪丸中未觀察到顯著的脂質變化。 總體而言，本研究利用核磁共振為基礎的脂質體學方法揭示了PFDA誘導大鼠多個器官的脂質變化。結果顯示PFDA暴露對肝臟和心臟的脂質變化影響較大，暗示著肝臟和心臟可能是主要的標的器官。我們的研究結果為未來PFDA在肝臟和心臟中毒理的機制研究提供了一個方向。

Per- and polyfluoroalkyl substances (PFASs) are a class of synthetic chemicals widely used in industrial and consumer products. Previous studies have reported associations between PFASs and metabolic syndromes, such as lipid metabolism disorders, and other adverse health effects. As a type of PFASs, perfluorodecanoic acid (PFDA) was recently reported in approximately 70% of Taiwanese children’s serum samples. However, research on PFDA is limited, and its toxicity and underlying mechanisms remain unclear. Therefore, this study aimed to investigate the lipid response of PFDA exposure on multiple organs of rats using lipidomic approaches in order to identify target organs and understand lipid effects and possible adverse health effects. Eighteen male Sprague-Dawley rats were administered with doses of 0, 0.5, and 1 mg/kg body weight of PFDA by oral gavage daily for 21 days. Changes of body weight and organ weight were measured. Subsequently, the rats were sacrificed, and the liver, heart, kidney, testis, pancreas, and lung were collected and extracted for nuclear magnetic resonance (NMR)-based lipidomics to identify key lipid responses. The obtained spectra were processed followed by multivariate analysis including partial least squares discriminant analysis (PLS-DA) and univariate analysis were conducted after spectral pretreatment followed by data interpretation. After treatment, significant increases were observed in the liver and the ratio of liver to body weight. PLS-DA models from the analysis of lipids revealed dose-dependent responses in the liver and heart after exposure to PFDA. The levels of cholesterol, and PC/PE were decreased, while the levels of FA was increased in the liver. In the heart, decreased GLs level and increased GPs level were observed. These lipid alterations in the liver may be associated with cell membrane dysfunction and mitochondrial dysfunction; while lipid changes in the heart may be associated with cardiovascular-related diseases. No significant lipid changes were observed in the lung, kidney, pancreas, and testis from the rats treated with PFDA. In conclusion, this study utilized NMR-based lipidomics to reveal lipid changes in multiple organs induced by PFDA exposure in rats. The results suggest that PFDA exposure has a greater impact on lipid changes in the liver and heart, implying that these organs may be the primary target organs. Our findings suggest the possible mechanisms of PFDA in the liver and the heart for future mechanism study.